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The role of Tregs and lipid mediators in the progression of Mycobacterium leprae infection to active disease

Award Number: R01AI129835
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Mycobacterium leprae, the causative agent of leprosy, is a highly infectious obligate intracellular bacterium. The vast majority of the individuals exposed to M. leprae becomes infected, but only a small proportion of the infected individuals evolves to active disease. Previous work in leprosy and tuberculosis demonstrated a major role of interferon-γ, an effector cytokine produced by pathogen-specific memory CD4 T cells, in the control of the infection by these intracellular pathogens. Our preliminary data show a progressive reduction in M. leprae-specific IFNγ levels in individuals that correlates to indicators of level of exposure to M. leprae and to bacillary load in individuals with leprosy. When we evaluated the interaction of M. leprae with Schwann cells and mononuclear phagocytes, we observed an induction of the anti-inflammatory cytokine IL-10 and the lipid mediator PGE-2. Metabolomics analyses of lesions and sera from leprosy patients also demonstrated clear differences in the presence of polyunsaturated fatty acid (PUFA) derived lipid mediators that correlated to the clinical forms of leprosy and bacillary loads. Other investigators detected frequencies of Foxp-3 positive T cells in the blood and lesions of leprosy patients that correlate to the expected inhibition of cellular immunity and effector function against M. leprae in the multibacillary forms of leprosy. Taking in to account these findings, we hypothesize that M. leprae interactions with Schwann cells and mononuclear phagocytes generate a microenvironment via the activities of lipid mediator that facilitates the inhibition of pathogen-specific IFN-γ response by Treg. We will test these hypotheses in the experiments of the following specific aims: 1-Evaluate the phenotype and functionally the Treg present in the blood and skin lesions of M. leprae-infected individuals and leprosy patients, to define the role of Treg in Th1 regulation during leprosy disease. 2- Investigate specific lipid mediators of inflammatory and immune responses and their alteration of the immune responses in M. leprae- infected individuals. Negative regulation of the immune response entails several different mechanisms that are present but less visible in asymptomatic individuals in the initial stages of the silent, long-evolving steps of chronic infections, autoimmune diseases, and cancer. Looking at changes in regulatory T responses that precede the onset of active disease using epidemiological and functional data as clues has the potential for reducing the individual and economic costs associated to these major health problems.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2021	FUNDACAO OSWALDO CRUZ	AVENIDA BRASIL 4365 QUININO, SALA 303	RIO DE JANEIRO				BRA	Allergy and Infectious Diseases Research	000	5	10/29/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	FUNDACAO OSWALDO CRUZ	AVENIDA BRASIL 4365 QUININO, SALA 303	RIO DE JANEIRO				BRA	Allergy and Infectious Diseases Research	000	5	7/12/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $143,706 )
2021	2021	FUNDACAO OSWALDO CRUZ.	AV. BRASIL 4.365, C. DE REL. INTE. EM SAUDE	RIO DE JANEIRO	RJ			BRA	Allergy and Infectious Diseases Research	000	5	8/31/2021	NON-COMPETING CONTINUATION	$143,706
														Subtotal = $143,706

Issue Date FY: 2020 ( Subtotal = $143,723 )
2020	2020	FUNDACAO OSWALDO CRUZ.	AV. BRASIL 4.365, C. DE REL. INTE. EM SAUDE	RIO DE JANEIRO	RJ	21040-360		BRA	Allergy and Infectious Diseases Research	000	4	3/17/2020	NON-COMPETING CONTINUATION	$143,723
														Subtotal = $143,723

Issue Date FY: 2019 ( Subtotal = $143,739 )
2019	2019	FUNDACAO OSWALDO CRUZ.	AV. BRASIL 4.365, C. DE REL. INTE. EM SAUDE	RIO DE JANEIRO	RJ	21040-360		BRA	Allergy and Infectious Diseases Research	000	3	3/21/2019	NON-COMPETING CONTINUATION	$143,739
														Subtotal = $143,739

Issue Date FY: 2018 ( Subtotal = $143,757 )
2018	2018	FUNDACAO OSWALDO CRUZ.	AV. BRASIL 4.365, C. DE REL. INTE. EM SAUDE	RIO DE JANEIRO	RJ	21040-360		BRA	Allergy and Infectious Diseases Research	000	2	3/29/2018	NON-COMPETING CONTINUATION	$143,757
														Subtotal = $143,757

Issue Date FY: 2017 ( Subtotal = $146,143 )
2017	2017	FUNDACAO OSWALDO CRUZ.	AV. BRASIL 4.365, C. DE REL. INTE. EM SAUDE	RIO DE JANEIRO	RJ	21040-360		BRA	Allergy and Infectious Diseases Research	000	1	4/25/2017	NEW	$146,143
2017	2017	FUNDACAO OSWALDO CRUZ.	AV. BRASIL 4.365, C. DE REL. INTE. EM SAUDE	RIO DE JANEIRO	RJ	21040-360		BRA	Allergy and Infectious Diseases Research	001	1	8/25/2017	NEW	-$146,143
2017	2017	FUNDACAO OSWALDO CRUZ.	AV. BRASIL 4.365, C. DE REL. INTE. EM SAUDE	RIO DE JANEIRO	RJ	21040-360		BRA	Allergy and Infectious Diseases Research	002	1	8/28/2017	NEW	$146,143
														Subtotal = $146,143

Grand Total All Awards = $721,068

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The role of Tregs and lipid mediators in the progression of Mycobacterium leprae infection to active disease

Award Number: R01AI129835

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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